The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of 51 Cr-ethylene diamine tetraacetate ( 51 Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. Conclusions: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition.
See EASL News, page 221Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are increasingly relevant public health issues owing to their close association with the worldwide epidemics of diabetes and obesity. NAFLD/NASH is one of the most common chronic liver diseases and increases the 5-year direct and indirect health care costs by an estimated 26% [1]. Although evidencebased clinical practice guidelines for this condition are badly needed, currently not enough evidence is available to formulate guidelines in an unbiased, responsible, and unequivocal way. This position statement summarizes the proceedings of the 2009 EASL Special Conference on NAFLD/NASH and proposes expert opinion for different aspects of the clinical care of these patients. Definition and classification of NAFLD/NASHNAFLD designates a condition characterized by excessive fat accumulation (steatosis). NASH defines a subgroup of NAFLD where steatosis coexists with liver-cell injury and inflammation (steatohepatitis).Primary NAFLD/NASH is associated with insulin resistance (IR) and its phenotypic manifestations. Secondary NAFLD/NASH is rare in adults, is unrelated to insulin resistance or the metabolic syndrome, and is due to a number of medical or surgical conditions or drug intake. Historically, primary NAFLD/NASH required the exclusion of other causes of liver disease (viral, autoimmune, genetic, etc.) and a daily alcohol consumption 620 g in women and 30 g in men, based on epidemiological studies showing that alcohol-induced steatosis can occur above these thresholds [2]. Owing to its increasing prevalence and strong association with the metabolic syndrome [3], it is now recognized that NAFLD/ NASH can occur together with other chronic liver diseases and that in some cases (chronic hepatitis C [4], hemochromatosis [5], alcoholic liver disease [6]) this can exacerbate liver damage [7]. This strongly argues for a change in nomenclature (such as metabolic fatty liver disease and metabolic steatohepatitis) which would drop the ''negative" definition of ''nonalcoholic" and would recognize the likely causal role of IR in NAFLD/NASH. Epidemiology of NAFLDThe prevalence of NAFLD in the general population assessed by ultrasonography is 20-30% in Europe [8,9] and the Middle East [10], 15% in the Far East [11,12], and 16% in some studies of normal weight subjects without metabolic risk factors [2]. A similar prevalence of 15-25% was documented histologically by older, post-mortem studies [13,14]. A surprisingly high prevalence of histological NAFLD has been described in apparently healthy living liver donors: 12-18% in Europe [15,16] and 27-38% in the US [15,17,18]. With sensitive technique such as MR spectroscopy, 34% of US adults have NAFLD [19]. Interestingly, 39% of newly identified cases of chronic liver disease in a US survey had NAFLD [20] which makes NAFLD/NASH one of the top causes of liver disease in Western countries.Recent studies in tertiary-care centers, using current histological definitions, have shown a surp...
Introduction: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population. Methods: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6-9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients. Results: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p,0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p,0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6-9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment. Conclusions: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.
: While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non‐alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF‐α, transforming growth factor‐β, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.
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